This Program is designed to determine how best to manipulate the immune system so that it can reject or destroy any material it sees as foreign including malignant cells that express neoantigens. Towards this end we plan (1) to produce antibodies (allo, hetero, and monoclonal) that recognize cell surface determinants expressed on some, but not all, T cells. (2) To use these antibodies to isolate and/or delete T cell subsets with unique immunoregulatory functions. (3) To produce antigen specific T cell clones, also with defined functions. (4) To determine the functions of the isolated cells and characterize their interactions with other cellular isolates. (5) To isolate the antigen specific molecular mediators these cells use to perform their immunological duties. (6) To characterize the mediators biological mechanism(s) of action as well as their chemical constitution. (7) To produce antisera (allo, hetero, or monoclonal) against these mediators to find unique antigenic specificities which mark the mediators unique biological functions. (8) To use these antisera, a) to isolate and chemically characterize the mediators counterparts on T cell membranes (e.g. antigen receptors), b) to further our goals of isolating functionally distinct T cell subsets and, c) to use as reagents (agonists or antagonists) which can modify in vivo immune responses in a predictable and desirable fashion. The achievement of these goals will lead to an increase in our basic understanding of immune regulation from which rational approaches towards immunomodulation can be designed.